5-aryl and arylphenyl sulfonic acids in treating inflammation

ABSTRACT

5-Aryl and heteroarylphenyl sulfonic acids and their derivatives are described and the processes for preparing the same are disclosed. These compounds exhibit anti-inflammatory properties and also possess an effective degree of anti-pyretic and analgesic activity.

United States Patent Sarett et al. [4 1 Sept. 12, 1972 [54] S-ARYL AND ARYLPHENYL SULFONIC [51] Int. Cl. ..A6lk 27/00 ACIDS IN TREATING INFLAMMATION [58] Field of Search ..260/512 R, 479 R; 424/303 [72] Inventors: Lewis H. Sarett Rolling Hill Road,

Skillman, NJ. 0 8558; John Hannah, [56] Reierems 155 ldlebrook Lane, Matawan, NJ. UNITED STATES PATENTS 07747 2 ,334 3 1968 D G t ..260/512 R 22 Filed: April 20, 1970 I e e [21] Appl. No.: 30,325 Primary Examiner-Stanley J. Friedman Attorney-Michael C. Sudol, Jr., Harry E. Westlake, Related US. Application Data J and wolk, Louis 63 Contin ti rt fS N 836,610, J l 1 25, 196; on m pa 0 er 0 57 ABSTRACT 5-Aryl and heteroarylphenyl sulfonic acids and their [52] US. Cl. ..424/303, 424/247, 424/250,

derivatives are described and the processes for preparing the same are disclosed. These compounds exhibit anti-inflammatory properties and also possess an effective degree of anti-pyretic and analgesic activity.

5 Claims, No Drawings S-ARYL AND ARYLPIIENYL SULFONIC ACIDS IN TREATING INF LAMMATION CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of our copending US. application Ser. No. 836,610 filed June 25, 1969.

BACKGROUND OF THE INVENTION There has been much emphasis during the past two decades to synthesize anti-inflammatory compounds. Many of those agents developed have been highly effective steroids, but are complex in structure. The most desirable anti-inflammatory agent should be relatively active and simple in structure.

SUMMARY OF THE INVENTION This invention is new 5-aryl and heteroaryl phenyl sulfonic acid compounds and their derivatives, as well as the processes for preparing these compounds and their use as medicinal agents. In particular, new 5-aryl and heteroaryl-Zhydroxypnenyl sulfonic acids and derivatives are the object of this invention. We have found that the compounds of this invention contain a useful degree of anti-inflammatory activity and effectively prevent and inhibit edema and granuloma tissue formation. These compounds further contain a moderate degree of anti-pyretic and analgesic activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS New S-aryl and heteroaryl phenyl sulfonic acid compounds and their derivatives are described in this invention. More specifically, this invention describes new S-aryl and heteroaryl-Z-hydroxyphenyl sulfonic acid derivatives and further relates to the non-toxic pharmaceutically acceptable salts, esters and amides of the sulfonic acids, as well as the various ether derivatives. Included also in this invention are their methods of preparation and their treatment as medicinal agents.

In a more narrow aspect, the present invention embraces those compounds having the following structural formula I lower alkoxy such as methoxy, ethoxy, etc.), nitro,

amino, alkylamino (preferably lower alkylamino such as methylamino, ethylamino, etc.), dialkylamino (preferably dilower alkylamino such as dimethylamino, methylethylamino, etc.), alkylthio (preferably lower alkylthio such as methylthio,

eth ylthio, etc.), alkylsulfonyl (preferably lower alkylsulfonyl such as methylsulfonyl), alkylsulfenyl (preferably lower alkylsulfenyl such as methylsulfenyl) and sulfamyl;

R is OH,

OM where M in general is any base which will form an acid addition salt with a sulfonic acid and whose pharmacological properties will not cause an adverse physiological effect when ingested by the body system (preferably an alkali, alkaline earth or aluminum metal such as sodium, potassium, calcium, magnesium and aluminum metals),

OR' where R is alkyl (preferably lower alkyl such as methyl, ethyl, propyl, i-propyl, etc.), aryl (preferably mononuclear aryl such as phenyl, tolyl, xylyl, etc.), aralkyl (preferably arlower alkyl such as benzyl, phenethyl, etc.

where R, and R are hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, etc.), cycloalkyl (preferably cyclolower alkyl such as cyclopropyl, cyclobutyl, etc.), aryl (preferably phenyl), aralkyl (preferably arlower alkyl such as benzyl, phenethyl, etc.); R and R may be the same or different and when taken together form a heterocyclic ring such as N-piperidino, N- morpholino, N-piperazino, N-homopiperazino, N-pyrrolidino, etc.; and R is hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, i-propyl, etc.), aralkyl (preferably arlower alkyl such as benzyl, phenethyl, etc.), or acyl (preferably lower acyl such as formyl, acetyl, propionyl, butyryl, etc.). The more preferred compounds of this invention embrace those compounds of the structural formula I where Ar is phenyl or 4-pyridyl; R is halo, diloweralkylamino or loweralkoxy; R is OH, OM, -OR' where R is lower alkyl, --NH where R and R are lower alkyl; and

R is hydrogen or acetyl.

The most preferred compounds of this invention embrace those compounds of the structural formula I where Ar is phenyl; R is halo; R, is OH and R is hydrogen. I

Representative compounds of this invention are as follows:

2-hydroxy-5-(p-fluorophenyl)phenyl sulfonic acid 2-acetoxy-5-(p-fluorophenyl)phenyl sulfonic acid 2-hydroxy-5-(p-methoxyphenyl)phenyl sulfonamide sodio 2-acetoxy-5-(p-chlorophenyl)phenyl sulfonic acid 2-methoxy-5-(p-nitrophenyl)phenyl sulfonic acid 2ethoxy-5-(o-methylphenyl)phenyl-N-phenyl sulfonamide 2-ethoxy-5-(a-naphthyl)phenyl-N-piperidino sulfonamide which is known to correlate well with anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activities. This is outlined in detail by C. A. Winter, Proc. Soc. Exptl. Biolog. & Med., 1962, Ill, 544. This test shows the correlation between clinically active compounds such as lndocin, Aspirin, Butazolidin, Tandearil, Cortone, Hydrocortone, Decadron and those of unknown activity. In view of results from tests such as this, the compounds of this invention can be considered to be active anti-inflammatory agents.

We have found that the compounds described in this invention have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formulation. In addition, they have a useful degree of anti-pyretic and analgesic activity. For these purposes, they may be administered orally, topically, parenterally or rectally. Orally, they may be administered in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities to be used will depend on the compound employed and the particular type of disease treated, oral dose levels of preferred compounds in the range of 0.5-30 mg./kg. (preferably in the range of 3-15 mg./kg. per day) are useful in control of arthritic conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient. Comparable dosages may be used when the administration is topically, parenterally or rectally.

The compounds of the present invention have further been found to show diuretic, anti-fibrinolytic and hypo-glycemic activity and when used for these utilities the same dosage ranges and conditions described above for anti-inflammatory activity will apply. Sulfonation of a 4-aryl or heteroaryl phenol or its ether derivatives readily takes place at the ortho position using mild sulfonating conditions. One such suitable method is treatment with concentrated sulfuric acid at mild temperatures (preferably l550C.). The alkoxy or aralkoxy groups may then be hydrolyzed back to the phenol by known methods such as with the use of boron trihalide, boron trichloride or trifluoride. It is preferred that the sulfonation take place on the isopropoxy derivative which is then easily hydrolyzed using mild conditions.

The 5-aryl or heteroaryl-Z-hydroxyphenylsulfonic acid may the be acylated to prepare the desired S-aryl or heteroaryl-2-acyloxyphenylsulfonic acids. One such method is by acylation with a suitable anhydride such as acetic anhydride in an aqueous alkaline solution to obtain S-aryl or heteroaryl-2-acetoxyphenylsulfonic acids. These reactions may be illustrated by the followingequations:

where Ar and R are as described above; Y is hydrogen. alkyl or aralkyl; and Z is acyl.

The sulfonic acid esters are conveniently prepared by reacting 5-aryl or heteroaryl-2-alkoxyphenyl sulfonyl halide with the proper alcohol of the formula R'OH. It is preferred to carry out this esterification in a basic medium such as anhydrous alcoholic alkaline or amine solution. The following equations illustrate these reactions:

SOzOR to give the desired sulfonamide. If desired, the alkoxy group can be hydrolyzed back to the phenol by known methods (such as with boron trichloride or trifluoride) and then acylated (such as with a suitable anhydride) to the desired S-aryl or heteroaryl-Z-acyloxyphenyl sulfonamides. The following equations illustrate these reactions:

to the corresponding aniline is-carried out by conventional methods. This is then diazotized to the desired phenol, which can then be alkylated or acylated by known methods. A detailed description of this preparation follows. Example I 5-(p-fluorophenyl)-2 hydroxyphenyl sulfonic acid EXAMPLE l-l 4-(p-fluorophenyl)aniline To 10.9 of 4-(p-fluorophenyl)nitrobenzene in 350 ml. of ethanol is added 1.5 g. of platinum oxide and this is reduced over hydrogen. The reaction mixture is then filtered through a pad of filter cel and evaporated in vacuo to yield 4-(p-t'luorophenyl)aniline. 4-(p-fluorophenyl)phenol A solution of 32.66 grams of 4-(p-fluorophenyl)- aniline in 120 ml. of glacial acetic acid is cooled to l-20C. To this solution is added slowly a solution of [2.25 grams of sodium nitrite in 120 ml. of water with stirring and continued cooling. Five minutes after this addition, the suspension of the diazonium acetate is added slowly to a boiling solution of 100 ml. of concentrated sulfuric acid and 200 ml. of water. After the final addition of the diazonium salt, the suspension is boiled for an additional minutes and then allowed to cool to room temperature. The reaction mixture is then filtered and the cake dried in vacuo to yield 4-(pfluorophenyl)-phenol (m.p. l52-l 61C.).

When the compounds of Table 1 below are substituted for 4-(p-fluorophenyl)nitrobenzene in the above example, the corresponding phenol of Table ll below is prepared.

TABLE I 4-(p-chlorophenyl)nitrobenzene 4-( 2,6-dichlorophenyl)nitrobenzene 4-(p-bromophenyl)nitrobenzene 4-(o-methylphenyl)nitrobenzene 4-( 3,4,S-trimethylphenyl)nitrobenzene 4-( p-methoxyphenyl)nitrobenzene 4 (p-dimethylaminophenyl)nitrobenzene 4-(p-trifluoromethylphenyl)nitrobenzene 4-( p-mercaptophenyl)nitrobenzene 4-(a-naphthyl )nitrobenzene 4(styryl )nitrobenzene 4-2-pyridyl)nitrobenzene 4-( 3pyridyl )nitrobenzene 4-(4-pyridyl)nitrobenzene 4-( 2-thienyl )nitrobenzene 4-( 3-thienyl)nitrobenzene TABLE ll 4-(p-chlorophenyl)phenol 4-( 2,6-dichlorophenyl )phenol 4-(p-bromophenyl)phenol 4-(o-methylphenyl)phenol yl)phenol 4-( p-methoxyphenyl)phenol 4-( 3,4,5-trimethylphen- 4-(p-dimethylaminophenyl)phenol 4-(p-trifluoromethylphenyl)phenol 4-(p-mercaptophenyl)phenol 4-(oz-naphthyl')phenol 4-(styryl)phenol 4-(2-pyridyl)phenol 4-( 3-pyridyl)phenol 4-(4-pyridyl)phenol 4-(2-thienyl)phenol I v I The ether derivatives may then be prepared by conventional methods using the suitable alkyl or aralkyl reagent, or the acyl derivatives may be directly made using conventional acylating reagents.

The following are detailed examples which show the preparation of the various compounds described in this invention. They are to be construed as illustrations of said compounds and not as limitations thereof.

" EXAMPLE I-2 When an equimolar amount of 4'-nitro-4-hydroxybiphenyl is used in place of 4'-fluoro-4-hydroxybiphenyl in the above example, the product obtained is 4-(pnitrophenyl)isopropoxybenzene.

When an equimolar amount of the 4-arylphenol compounds of Table II, Example [-1, are used in place of 4'-fluoro-4-hydroxybiphenyl in the above example, the corresponding compound of Table 1 below is prepared.

TABLE I 4-(p-chlorophenyl)isopropoxybenzene 4-( 2,6-dichlorophenyl )isopropoxybenzene 4-(p-bromophenyl)isopropoxybenzene 4-(o-methylphenyl)isopropoxybenzene 4-( 3 ,4,5-trimethylphenyl )isopropoxybenzene 4-( p-methoxyphenyl isopropoxybenzene 4-(p-dimethylaminophenyl)isopropoxybenzene 4-(p-trifluoromethylphenyl)isopropoxybenzene below is prepared.

4-(p-chlorophenyl)methoxybenzene 4-(o-methylphenyl)ethoxybenzene 4-(p-methoxyphenyl)methoxybenzene 4-(p-trifluoromethylphenyl)methoxybenzene 4-(a-naphthyl)ethoxybenzene 4-styryl0benzyloxybenzene 4-(p-nitrophenyl)methoxybenzene 4-p-nitrophenyl)benzyloxybenzene 4-(3-pyridyl)metl1oxybenzene 4-(4-pyridyl)benzoyloxybenzene 4-( 2-thienyl )ethoxybenzene EXAMPLE l-3 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonic acid 4'-Fluoro-4-isopropoxybiphenyl (8.0 g.) is added to sulfuric acid (25 ml., density l.84)at 20. The mixture is then heated to 80 with stirring in minutes, held at this temperature for 10 minutes, and poured onto ice. The precipitate of 4-(p-fluorophenyl)-2-isopropoxyphenylsulfonic acid is filtered off, washed with water, and dried in vacuo.

When an equimolar amount of the 4-aryl and heteroaryl phenyl ethers of Example 1-2 are used in place of 4'-fluoro-4-isopropoxybiphenyl in the above example, the corresponding sulfonic acid of Table I TABLE] I 5-(p-nitrophenyl)-2-isopropoxyphenyl sulfonic acid 5-(p-chlorophenyl)-2-isopropoxyphenyl sulfonic acid 5-(2,-dichlorophenyl)-2-isopropoxyphenyl sulfonic acid 5-(p-bromophenyl)-2-isopropoxyphenyl sulfonic acid 5'(o-methylphenyl)-2-isopropoxyphenyl sulfonic acid 5-(3,4,5-trimethylphenyl)-2-isopropoxyphenyl sulfonic acid 5-(p-methoxyphenyl)-2-isopropoxyphenyl sulfonic acid 5-(p-dimethylaminophenyl)-2-isopropoxyphenyl sulfonic acid 5-(p-trifluoromethylphenyl)-2-isopropoxyphenyl sulfonic acid 5-(a-naphthyl)-2-isopropoxyphenyl sulfonic acid 5-styryl-2-isopropoxyphenyl sulfonic acid 5-(Z-pyridyl)-2-isopropoxyphenyl sulfonic acid 5-(3-pyridyl)-2-isopropoxyphenyl sulfonic acid 5-(4-pyridyl)-2-isopropoxyphenyl sulfonic acid 5-(2-thienyl)-2-isopropoxyphenyl sulfonic acid 5-( 3-thienyl)-2-isopropoxyphenyl sulfonic acid 5-(p-fluorophenyl)-2-methoxyphenyl sulfonic acid 5-(p-fluorophenyl)-2-t-butoxyphenyl sulfonic acid 5-(p-fluorophenyl)-2-benzyloxyphenyl sulfonic acid 5-( p-chlorophenyl)-2-methoxyphenyl sulfonic acid 5(o-methylphenyl)-2-ethoxyphenyl sulfonic acid 5(p-methoxyphenyl )-2-methoxyphenyl sulfonic acid 5-(p-trifluoromethylphenyl)-2-methoxyphenyl sulfonic acid S-(a-naphthyl)-2-ethoxyphenyl sulfonic acid S-styryl-2-benzyloxoyphenyl sulfonic acid 5-( p-nitrophenyl)-2-methoxyphenyl sulfonic acid 5-( p-nitrophenyl)-2-benzyloxyphenyl sulfonic acid 5-(3-pyridyl)-2-methoxyphenyl sulfonic acid 5-(4-pyridyl)Q-benzyloxyphenyl sulfonic acid 5-(2-thienyl)-2-ethoxyphenyl sulfonic acid.

EXAMPLE [-4 S-(p-fluorophenyl)-2-hydroxyphenyl sulfonic acid 5-(pfluorophenyl)-2-isopropoxyphenyl sulfonic acid (5.0 g.) is dissolved in hot aqueous 48 percent hydrobromic acid (25 ml.) and the solution heated to reflux for a few minutes, and then cooled to room tem- 'perature. The mixture is evaporated to dryness at -40/0.l mm pressure, and the residue crystallized from aqueous ethanol to yield 4-(p-fluorophenyl)-2- hydroxyphenyl sulfonic acid.

When an equimolar amount of the compounds of Table I Example [-3 are used in place of 5-(pfluorophenyl)-2-isopropoxyphenyl sulfonic acid in the above example, the corresponding product of Table I below is prepared.

TABLE I S-(p-nitrophenyl)-2-hydroxyphenylsulfonic acid S-(p-chlorophenyl)-2-hydroxyphenylsulfonic acid 5-(2,6-dichlorophenyl)-2-hydroxyphenylsulfonic acid 5-( p-bromophenyl)-2-2-hydroxyphenylsulfonic acid 5-(o-methylphenyl)-2-hydroxyphenylsulfonic acid 5-( 3,4,5-trimethylphenyl )-2-hydroxyphenylsulfonic acid 5-(p-methoxyphenyl)-2-hydroxyphenylsulfonic acid 5-(p-dimethylaminophenyl)-2-hydroxyphenylsulfonic acid hydrobromide 5-(p-trifluoromethylphenyl)-2-hydroxyphenylsulfonic acid S-(a-naphthyl)-2-hydroxyphenylsulfonic acid 5-styryl-2-hydroxyphenylsulfonic acid 5-(2-pyridyl)-2-hydroxyphenylsulfonic acid 5-( 3-pyridyl)-2-hydroxyphenylsulfonic acid 5-(4-pyridyl)-2-hydroxyphenylsulfonic acid 5-(2-thienyl)-2-hydroxyphenylsulfonic acid 5-( 3-thienyl)-2-hydroxyphenylsulfonic acid EXAMPLE I-5 4'Fluoro-4-hydroxybiphenyl (8 g.) is added to sulfuric acid (25 ml., density l.84)at 20. The mixture is stirred at 40' for 20 minutes then poured into ice. Precipitated 5-(p-fluorophenyl)-2-hydroxyphenyl sulfonic acid is filtered off, washed with a little water, and dried in vacuo.

When an equimolar amount of the 4-aryl orheteroaryl phenol compounds of Table II, Example [-1,

are used in the above example in place of 4-fluoro-4- hydroxybiphenyl, the corresponding sulfonated product is obtained.

EXAMPLE I] 5-(p-Fluorophenyl)-2-acetoxybenzene sulfonic acid A mixture of -(p-fluorophenyl)-2-hydroxyphenyl sulfonic acid (2 g.), acetic anhydride (4 ml.), and phosphoric acid (0.2 ml.) is heated to 100 for minutes. The mixture is cooled to 80 and water (2 ml.) is added in one portion down the condenser, vigorously decomposing the excess acetic anhydride. More water (10 ml.) is added and the mixture cooled to 0. Precipitated 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonic acid is filtered off, and recrystallized from an anhydrous benzene-cyclohexane mixture.

When an equimolar amount of the compounds of Table l Example l-4 are used in place of 4-(pfluorophenyl)-2-hydroxyphenyl sulfonic acid, the corresponding product of Table 1 below is prepared.

TABLE I 5-(p-nitrophenyl)-2-acetoxyphenyl sulfonic acid 5-(p-chlorophenyl)-2-acetoxyphenyl sulfonic acid 5-(2,6-dichlorophenyl)-2-acetoxyphenyl sulfonic acid 5-(p-bromophenyl)-2-acetoxyphenyl sulfonic acid 5-( o-methylphenyl )-2-acetoxyphenyl sulfonic acid 5-( 3,4,5 trimethylphenyl)-2-acetoxyphenyl sulfonic acid 5-(p-methoxyphenyl)-2-acetoxyphenyl sulfonic acid 5-(p-dimethylaminophenyl)-2-acetoxyphenyl sulfonic acid 5-(p-trifluoromethylphenyl)-2-acetoxyphenyl sulfonic acid 5-(a-naphthyl)-2-acetoxyphenyl sulfonic acid 5-(styryl)-2-acetoxyphenyl sulfonic acid 5-(2-pyridyl)-2-acetoxyphenyl sulfonic acid 5-( 3-pyridyl)-2-acetoxyphenyl sulfonic acid 5 -(4-pyridyl)-2-acetoxyphenyl sulfonic acid 5-( 2-thienyl)-2-acetoxyphenyl sulfonic acid 5-( 3-thienyl)-2-acetoxyphenyl sulfonic acid When an equimolar amount of propionic anhydride, butyric anhydride, or crotonoic anhydride are used in place of acetic anhydride in the above example, the corresponding S-aryl or heteroaryl-Z-propionlyoxy, 2- butyryloxy and 2-crotonyloxyphenyl sulfonic acid is prepared. A representative list of these compounds is shown below in Table II.

chloride Chlorosulfonic acid (0.3 mole) is added slowly to a continuously stirred solution of 4'-fluoro-4-isopropoxybiphenyl (0.1 mole) in carbon tetrachloride (200 ml.) at a rate which does not allow the internal temperature to rise above 25 (cool if necessary). The mixture on completion is stirred for an additional 2 hours at room temperature, then stirred vigorously with crushed ice g.) for one minute. The carbon tetrachloride layer is quickly separated, washed once with dilute aqueous sodium carbonate, dried for a few minutes over magnesium sulfate, filtered, and evaporated in vacuo, leaving 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonyl chloride of sufficient purity to be used directly in the following examples Ill-2 and V-l.

When the compounds of Example l-2 are used in place of 4'-fluoro-4-isopropoxybiphenyl in the above example, the corresponding chlorosulfonated product is prepared.

EXAMPLE III-2 S-(p-Fluorophenyl)-2-isopropoxyphenyl sulfonamide 5-(p-Fluorophenyl)-2-isopropoxyphenyl sulfonyl chloride (2 g.) isvigorously shaken with an excess of concentrated aqueous ammonia (10 ml.) at room temperature for 5 minutes. The mixture is diluted with water (10 ml.) and 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonamide is filtered off, washed with water, and recrystallized from aqueous ethanol.

When the sulfonyl chloride compounds of Example 6 are used in place of 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonyl chloride in the above example, the corresponding sulfonamides are prepared.

When methylamine, dimethylamine, cyclopropylamine, cyclohexylamine, aniline, benzylamine, piperidine, morpholine, piperazine,

homopiperazine or pyrrolidine are used in place of ammonia in the above example, the corresponding sulfonamides are prepared. A representative list is shown below.

N-methyl S-(p-fluorophenyl)-2-isopropoxyphenyl sulfonamide N,N-dimethyl S-(p-nitrophenyl)-2-methoxyphenyl sulfonamide N-cyclopropyl 5-(p-chlorophenyl)-2-isopropoxyphenylsulfonamide N-phenyl 5-(-methylphenyl)-2-ethoxyphenyl sulfonamide sul- 5-(p-methoxyphenyl-2-isopropox- -(p-Fluorophenyl)-2-hydroxyphenyl sulfonamide 5-(p-Fluorophenyl)-2-isopropoxyphenyl sulfonamide (2 g.) is dissolved in hot aqueous 48 percent hydrobromic acid (20 ml.). The solution is rapidly heated to reflux for 2 minutes, and cooled at once to room temperature. The mixture is evaporated to dryness at 20/0.l mm. pressure, and the residual 5'-(pfluorophenyl)-2-hydroxyphenyl sulfonamide recrystallized from aqueous ethanol.

When the sulfonamides of Example Ill-2 are used in the above example in place of 5-(p-fluorophenyl)-2- isopropoxyphenyl sulfonamide, the corresponding product below is prepared.

N-methyl-5-(p-fluorophenyl)-2-hydroxyphenyl sulfonamide N,N-dimethyl 5-(p-nitrophenyl)-2-hydyroxyphenyl sulfonamide N-cyclopropyl S-(p-chlorophenyl)-2-hydroxyphenyl sulfonamide N-phenyl 5-(o-methylphenyl)-2-hydroxyphenyl sulfonamide N,N-diphenyl 5-(p-methoxyphenyl)-2-hydroxyphenyl sulfonamide N-benzyl .5-(p-dimethylaminophenyl)-2-hydroxyphenyl sulfonamide N-piperidino S-(a-naphthyl)-2-hydroxyphenyl sulsul- 5-( Z-thienyl)-2-hydroxyphenyl EXAMPLE IV 5-(p-Fluorophenyl)-2-acetoxyphenyl sulfonamide A mixture of S-(p-fluorophenyl)-2-hydroxyphenyl sulfonamide (2g.), acetic anhydride (4 ml.) and phosphoric acid (0.2 ml.) is heated to 100 for 10 minutes. The mixture is cooled to 80 and water (2 ml.) added in one portion down the condenser. When the excess of acetic anhydride has decomposed more water 10 ml.) is added and the mixture cooled to 0. Precipitated 5-(p-fluorophenyl)- Z-acetoxyphenyl sulfonamide is filtered off, and is recrystallized from an anhydrous benzene-cyclohexane mixture.

When the sulfonamides of Example Ill-3 are used in place of 5-(p-fluorophenyl)-2-hydroxyphenyl sulfonamide in the above example, the corresponding product below is prepared.

N-methyl 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonamide N,N-dimethyl sulfonamide N-cyclopropyl 5-(p-chlorophenyl)- 2-acetoxyphenyl sulfonamide N-phenyl 5-(o-methylphenyl)-2-acetoxyphenyl sulfonamide 5-( p-nitrophe nyl )-2-acetoxyphenyl N,N-diphenyl 5-(p-methoxyphenyl)-2-acetoxyphenyl sulfonamide N-benzyl S-(p-dimethylaminophenyl)-2-acetoxyphenyl sulfonamide N-piperidino 5-(a-naphthyl)-2-acetoxyphenyl sulfonamide N-morpholino 5-styryl-2-acetoxyphenyl sulfonamide N-piperazino 5-(pfluorophenyl)-2-acetoxyphenyl sulfonamide N-homopiperazino 5-(p-trifluoromethylphenyl)-2 acetoxyphenyl sulfonamide N-pyrrolidino 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonamide N,N-dimethyl fonamide N-piperazino 5-(3-pyridyl)-2-acetoxyphenyl sulfonamide N,N-dicyclohexyl 5-( Z-thienyl)-2-acetoxyphenyl sulfonamide When propionic anhydride, butyric anhydride and crotonic anhydride are used in place of acetic anhydride the corresponding product is prepared.

EXAMPLE V Methyl S-(p-fluorophenyl)-2-acetoxyphenyl sulfonate EXAMPLE V-l 5-( p-fluorophenyl)-2-isopropoxyphenyl 5-(4-pyridyl)-2-acetoxyphenyl sul- Methyl fonate 5-(p-Fluorophenyl)-2-isopropoxyphenyl sulfonyl chloride (0.01 mole) is added in one portion to a solution of sodium methoxide (0.01 mole) in methanol (20 ml.) at room temperature. The mixture is stirred at room temperature for 30 minutes then evaporated to dryness in vacuo. The product is extracted from contaminating sodium chloride with anhydrous benzene. Evaporation of the benzene in vacuo leaves 5-(pfluorophenyl)-2-isopropoxyphenyl sulfonic acid methyl ester.

When the compounds of Example lIl-l are used in place of 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonychloride the corresponding methyl esters are prepared.

In the above example, when the sodium salts of ethanol, butanol, benzyl alcohol and phenol are used in place of sodium methoxide along with the appropriate alcohol in place of methanol, the corresponding sulfonic acid ester is prepared. A representative list of the compounds prepared is shown below.

methyl 5-(p-fluorophenyl)-2-methoxyphenyl fonate ethyl 5-(p-nitrophenyl)-2-methoxyphenyl sulfonate benzyl 5-(p-nitrophenyl)-2-benzyloxyphenyl sulfonate methyl S-(a-naphthyl)-2-isopropoxyphenyl sulfonate butyl 5-(p-dimethylaminophenyl)-2-isopropoxyphenyl sulfonate phenyl 5-(p-fluorophenyl)-2-isopropoxyphenyl sulfonate methyl 5-(p-trifluoromethylphenyl)-2-methoxyphenyl sulfonate sulfonate methyl 5-(p-methoxyphenyl)-2-isopropoxyphenyl sulfonate ethyl S-(o-methylphenyl)-2-ethoxyphenyl sulfonate methyl S-(p-mercaptophenyl)-2-isopropoxyphenyl sulfonate methyl 5-(4-pyridyl)-2-isopropoxyphenyl sulfonate sulsul-

benzyl -(3-pyridyl)-2-methoxyphenyl sulfonate phenyl 5-(4-pyridyl)-2-benzyloxyphenyl sulfonate methyl 5-(2-thienyl)-2-ethoxyphenyl sulfonate ethyl 5-(3-thienyl)-2-isopropoxyphenyl sulfonate EXAMPLE v-2 Methyl 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonate A solution/suspension of S-(p-fluorophenyD-Z- acetoxyphenyl sulfonic acid silver salt (prepared by adding an excess of silver nitrate to an aqueous solution of sulfonic acid and filtering off the precipitated salt) in a large excess of methyl iodide is stirred and refluxed for 1 hour. Silver salts are filtered off and solvent removed in vacuo leaving methyl 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonate.

When the sulfonic acids of Examples [-4 and II are used in place of 5-(p-fluorophenyl)-2-acetoxyphenyl sulfonic acid the corresponding methyl esters are prepared.

When ethyliodide, butyliodide, benzyliodide, phenethyl iodide and phenyl lithium are used in place of methyl iodide in the above example, the corresponding 2-acetoxy sulfonic acid ester is prepared. A representative list of the compounds prepared is shown below.

benzyl fonate methyl S-(p-nitrophenyl)-2-acetoxyphenyl sulfonate 5-(p-fluorophenyl)-2-acetoxyphenyl sulmethyl 5-(o-methylphenyl)-2-acetoxyphenyl sulfonate methyl 5(-p-methoxyphenyl)-2-acetoxyphenyl sulfonate methyl 5-(p-dimethylaminophenyl)-2-acetoxyphenyl sulfonate sulbenzyl 5-(p-fluorophenyl)-2-hydroxyphenyl sulfonate ethyl 5-(p-methoxyphenyl)-2-hydroxyphenyl sulfonate methyl 5-( a-naphthyl)-2-hydroxyphenyl sulfonate ethyl 5-styryl-2-hydroxyphenyl sulfonate methyl 5-(4-pyridyl)-2-hydroxyphenyl sulfonate phenyl 5-(3-pyridyl)-2-hydroxyphenyl sulfonate benzyl 5-(2-thienyl)-2-hydroxyphenyl sulfonate EXAMPLE Vl Sodio 5-(p-fluorophenyl)-2-hydroxy phenyl sulfonate To a solution of 0.001 mole of sodium hydroxide in ml. of water is added 0.001 mole of 5-(ptluorophenyl)-2-hydroxy phenyl sulfonic acid in 10 ml. of ethanol. The mixture is stirred, no need to heat, and evaporated in vacuo to obtain sodio S-(p-fluorophenyl)-2-hydroxy phenyl sulfonate.

When an equimolar amount of potassium hydroxide, lithium carbonate, aluminum hydroxide, sodium carbonate or calcium hydroxide are used in place of sodium hydroxide the corresponding salt is prepared.

When the 5-(p-fluorophenyl-Z-hydroxy phenyl sulfonic acid of the above procedure is replaced by any of the sulfonic acid compounds of this invention, the corresponding salt is prepared.

When two equivalents of the above bases are used in the above examples, the corresponding disalt is prepared.

The following representative examples illustrate the interconversion or introduction of functional groups which can be accomplished at various stages of the preparation of the final products.

Ethyl 5-(p-aminophenyl)-2-methoxyphenyl sulfonate A mixture of pure ethyl 5-(p-nitrophenyl)-2-methoxyphenyl sulfonate (0.01 mole) in methanol-dioxane (1:1) (ca. 200 ml.) is reacted with hydrogen at room temperature (40 p.s.i.) in the presence of 10 percent Pd/C (1.0 g.). The mixture is filtered, the cake washed well with methanol, the filtrate evaporated in vacuo, the residue chromatographed on a silica gel column using a methanol-methylene chloride system (v/v 0-30 percent methanol) as eluant to yield ethyl 5-(paminophenyl)-2-methoxyphenyl sulfonate.

Ethyl 5-( p-hydroxyphenyl)-2-methoxyphenyl sulfonate A mixture of ethyl 5-(p-amin0phenyl)-2-methoxyphenyl sulfonate (0.2 moles), water (600 ml.) and concentrated sulfuric acid (25 ml.) is cooled to 10C. and a solution of sodium nitrite (0.21 mole) in a minimum of water is added gradually. When the presence of free nitrous acid is detected (starch-iodide paper), the addition is stopped and the diazotization mixture is allowed to warm to room temperature, then heated on a steam-bath until there is no more nitrogen evolution. The mixture is cooled, extracted well with chloroform, the combined chloroform layer dried, concentrated to a residue, methanol (300 ml.) added plus 0.5 ml. concentrated sulfuric acid, the mixture heated gently for several hours, the mixture concentrated in vacuo to remove most of the methanol, the residue partitioned between chloroform-dilute sodium bicarbonate solution, the chloroform layer dried, filtered and concentrated to a residue. Chromatography of the residue on a silica gel column using an ether-petroleum ether (v/v 0-100 percent ether) system as eluant yields ethyl 5-(p-hydroxyphenyl)-2-methoxyphenyl sulfonate. Methyl S-(p-methylthiophenyl)-2-isopropoxyphenyl sulfonate A mixture of methyl 2-(pmercaptophenyl)-2- isopropoxyphenyl sulfonate (0.01 moles) in a deaerated aqueous KOl-l solution (0.01 mole) is treated with dimethylsulfate (0.012 mole) at room temperature over one hour, the mixture acidified, extracted well with ether, and the dried ether extracts chromatographed on a silica gel column using an etherpetroleum ether system (v/v 0-30 percent ether) as eluant yielding methyl 5-(p-methylthiophenyl)-2- isopropoxyphenyl sulfonate.

Methyl 5-(p-methylsulfinylphenyl)-2-isopropoxyphenylsulfonate To an ice-cooled solution of methyl 5-(pmethylthiophenyl)-2-isopropoxyphenyl sulfonate (0.01 mole) in methanol-acetone is added a solution of sodi- I um meta-periodate (0.01 mole) in a minimum of water,

or a non-toxic pharmaceutically acceptable salt where Ar is phenyl containing one or more R substituents which may be at any position on the ring;

R is'hydrogen, lower alkyl, lower alkenyl, halogen, haloloweralkyl, hydroxy, lower alkoxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, mercapto, lower alkylthio, lower alkylsulfonyl, lower alkylsulfenyl or sulfamyl;

R is OH, OR where R is lower alkyl, phenyl, or

phenyl-loweralkyl',

R is hydrogen, lower alkyl, phenyl-lower alkyl or lower alkanoyl.

2. The method of treating inflammation according to claim 1 where Ar is phenyl, R is halo, R is --OH, OR where R is lower alkyl, and R is hydrogen or lower alkanoyl.

3. The method of treating inflammation according to claim 1 where Ar is phenyl, R is p-fluoro, R is -OH, and R is hydrogen, thus administering the compound S-(p-fluorophenyl)-2-hydroxyphenyl sulfonic acid.

4. The method of treating inflammation according to claim 1 where Ar is phenyl, R is p'fluoro, R is -OH, and R is acetyl, thus administering the compound 5- (pfluorophenyl)-2-hydroxysulfonic acid.

5. The method of treating inflammation which comprises the administration to a patient, an effective amount of a compound of the formula where R is one or more halogen substituents which may be at any position on the ring.

Patent No. 3,69l l85 Dated S In n fl Lewis H. Barrett and .Tnhn Hannah It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 16, line 16, Claim 4, "hydroxysulfonic" should read --acetoxyphenylsulfonic--.

Signed and sealed this 30th day of January 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer 1 Commissioner of Patents 

2. The method of treating inflammation according to claim 1 where Ar is phenyl, R is halo, R1 is -OH, -OR'' where R'' is lower alkyl, and R2 is hydrogen or lower alkanoyl.
 3. The method of treating inflammation according to claim 1 where Ar is phenyl, R is p-fluoro, R1 is -OH, and R2 is hydrogen, thus administering the compound 5-(p-fluorophenyl)-2-hydroxyphenyl sulfonic acid.
 4. The method of treating inflammation according to claim 1 where Ar is phenyl, R is p-fluoro, R1 is -OH, and R2 is acetyl, thus administering the compound 5-(p-fluorophenyl)-2-hydroxysulfonic acid.
 5. The method of treating inflammation which comprises the administration to a patient, an effective amount of a compound of the formula where R is one or more halogen substituents which may be at any position on the ring. 